Upload
george-papageorgiou
View
217
Download
3
Embed Size (px)
Citation preview
Pergamon Tetrahedron 55 (1999) 237-254
TETRAHEDRON
Synthetic and Photochemical Studies of N-Arenesulfonyl Amino Acids
George Papageorgiou and John E.T. Corrie'
National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, U.K.
Received 26 August 1998; revised 12 October 1998; accepted 29 October 1998
Abstract: Near-UV irradiation of N-arenesulfonyl amino acids in aqueous solution in the presence of a water-soluble 1,5-dialkoxynaphthalene as light absorber and single electron source results in cleavage of the sulfonamide with very sub-stoichiometric release of the intact amino acid because of concurrent decarboxylation during photocleavage. In compounds with a single carboxylat¢ group ortho to the sulfonamide this decarboxylation is significantly suppressed, presumably because the additional carboxylate is a preferred target for the oxidative decarboxylation. However, release of free amino acid is at best 30% of the converted starting material and the yield is not further improved if the sulfonamide is flanked by two carboxylate groups. The data suggest that fragmentation of the initially generated sulfunamide radical anion occurs by two pathways, only one of which can be intercepted by an ortho- carboxylate. Synthetic routes to the 2,6-disubstituted arenesulfonamides are based on ortho-directed metalation reactions followed by quenching with SO 2 and efficient conversion of the resulting arenesulfinates to arenesulfonyl chlorides. © 1998 Elsevier Science Ltd. All rights reserved.
Keywords: Amino acids and derivatives; Decarboxylation; Photochemistry; Sulfonamides
I N T R O D U C T I O N
As part of our continuing development and application of photolabile precursors of biological effector
molecules, ~ colloquially known as caged compounds, 2 we required reagents that would release neuroactive
amino acids, particularly L-glutamate, upon irradiation. Other groups 35 have shared this goal with us ~7 but
compounds meeting the requirements of fast (sub-millisecond), efficient and localised release of an amino
acid, while themselves being stable to hydrolysis and having no agonist or antagonist properties, have
remained elusive. Based on earlier studies by Hamada et al.,* we have described photolabile sulfonamides that
appeared promising in terms of rapid and efficient photoconversion but that released grossly sub-
stoichiometric amounts of intact c~-amino acids because of concurrent decarboxylation during photolysis. 7
Suggested mechanisms of the expected reaction and the competing decarboxylation are shown in Scheme 1.
For the glycine derivative 1 (R = H) the yield of free glycine upon photolysis with near-UV light was only 6%
of the converted starting compound. Decarboxylation could not be prevented by addition of a large excess of
exogenous carboxylate salts (acetate or phenylacetate) but we suggested 7 that installation of an intramolecular
"sacrificial" carboxylate near the sulfonamide group might efficiently intercept the reactive sulfonyl radical
shown in Scheme 1, thereby enhancing the yield of intact amino acid. Synthesis and photochemistry of five
compounds bearing one or two such carboxylate groups are now reported. Photochemical results from these
0040-4020/99/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(98)01029-1
238 G. Papageorgiou, J. E. T. Corrie I Tetrahedron 55 (1999) 237-254
compounds indicate that this interception strategy is effective but that the photocleavage mechanism is more
complex than originally proposed, s
OMe
i O ~ hv =- S.E.T.
(CH2)3 [~ /.L OPO3 2- v,-~'~'SO2N HCHRCO 2
t
OMe
OMe
~ ' - - ~ NH3 +
+ + R/J~-CO~t OR'
S.E.T. ~ l ] ~ ' ~ O 2 Reduction [competing] / I expected I
Ii"~--~OMe + l pathway/J~ "~pathweyJ OMe
+ Rt]"C02 "C02
soi "SO- 2 product(s)
Schema I
RESULTS AND DISCUSSION
To evaluate our strategy we proposed to study several attachment modes of a potential sacrificial
carboxylate group and to minimise the synthetic effort we changed from the intramolecular photochemistry
shown in Scheme 1 to an intermolecular version, i.e. with the light aeceptor/electron donor as a separate
molecule to the arenesulfonamide. This intermolecular photochemistry has been previously established by
Hamada et al. ~ As indicated in Scheme 1, we felt that only the sulfonyl moiety would be involved in the
decarboxylation and therefore envisaged that the intermolecular reaction, although less efficient, would validly
probe the effects of carboxylate substitution. In practice it transpired that the intermolecular variant allowed
some additional insight on the photolysis mechanism (see below). For simplicity, glyeine was used as the
model amino acid throughout most of this work and we initially made compounds 2, 3 and 4 that were
derivatives of benzoic, phenylacetic and phenoxyacetic acids respectively. Compounds 2 and 3 were obtained
by minor variations of published procedures (see Experimental). Compound 4 was prepared as shown in
Scheme 2.
RI',,,,~SO2NHCH2CO:t H 2 R = CO2H, R 1 = H 3 R = CH2CO2H, R 1 = H
"~ R 4 R = OCH2CO2H, R 1 = Me
G. Papageorgiou, J. E. T. Corrie / Tetrahedron 55 (1999) 237-254 239
M e - ~ ~ n Me- '~,~,NHCH2CO2Me
6 7 R=Bn 8 R=H
.,,•OBn iv, v i, ii, iii m~'e" v -S02C I -"-
8
j~..OCH2CO2R ~
Me-"~,..~"~ SO2 N HC H 2 C O2 R 1
9 R=Et, R 1=Me 4 R, R1 =H
8¢heme 2: Reagents; i) n-BuLi-TMEDA; ii) SO2; iii), NCS; iv) Methyl glycinate.HCI-NMM; v) H2-Pd/C; vi) BrCH2CO2Et-DIPEA; vii) NaOH
The photochemistry of sulfonamides 2-4 had to bc studied in aqueous solution, since the intended
application was to living biological systems, and a water-soluble 1,5-dialkoxynaphthalene was needed as the
light-absorbing co-reagent. The known bis-carboxylic acid 10 and the bis-phosphatc 11 were prepared and
examined for photostability in pH 7 aqueous solution under ncar-UV irradiation. Under a standard set of
conditions used throughout this work and in the prescncc of atmospheric oxygen, 73% of the bis-carboxylate
10 was destroyed during a I0 rain irradiation, while only 21% of the bis-phosphate 11 was destroyed. The
greater instability of 10 probably arises from photo-dccarboxylation, as has been described for other
aryloxyacetic acids. 9 All subsequent experiments therefore uscd bis-phosphate 11 as the co-reagent.
0(CH2)3OPO3 2"
OCH2CO2H O(CH2)3OPO3 2"
Equimolar pH 7 aqueous solutions of 11 with each of the three sulfonamides 2-4 in turn were irradiated
and consumption of the sulfonamides was monitored by HPLC. As a control, a parallel experiment was
performed with N-tosylglycine. In all cases glycine formation was monitored by quantitative amino acid
analysis. All photolyses were conducted in the absence of a reducing agent such as ascorbate, ~'h since the aim
was to determine the efficacy of the intramolecular carboxylate group. Results are shown in Table 1, which
gives corresponding data for irradiation in the absence of the naphthalene 11. Several features are apparent.
First, the efficiency of glycine release (i.e. fractional formation of glycine per molecule of photolysed
sulfonamide) from N-tosylglycine was very low, in agreement with the intramolecular results. 7 Second,
photolysis of each of 2-4 in the presence of the naphthalene 11 gave a substantially higher efficiency of
glycine release (up to -7-fold) than was obtained from N-tosylglycine, suggesting that the intramolecular
carboxylate group was partially effective at intercepting decarboxylation of the photoreleased amino acid.
240 G. Papageorgiou, J. E. T. Corrie / Tetrahedron 55 (1999) 237-254
Third, the different compounds showed substantial differences in their photosensitivity, e.g. 2 was only one-
third photolysed in 15 rain while 4 was almost two-thirds photolysed in 3 min. Lastly each compound except
N-tosylglycine was photolysed to a similar extent whether or not 11 was present, though in every case the
yield of photoreleased glycine was greater when 11 was present. Features of these results are discussed below
in parallel with the data of Table 2.
Table 1. Theoretical and actual product yields for photolysis of N-tosylglycine and compounds 2-4
Compound Photolysis 11 Present % Photolysis" Glycine Actual Yield ° Time (min) Yield (o~)b Th~ol[~ti~l Yield
N-Tosylglycine 10 Yes 39.8 1.6 0.04 N-Tosylglycine 10 No 0 0
2 15 Yes 33.7 10.3 0.31 2 15 No 31.2 4.1 0.13 3 3 Yes 27.0 5.2 0.19 3 3 No 24.5 0.6 0.02 4 3 Yes 63.7 12.9 0.20 4 3 No 78.5 7.8 0.I0
• Consumption of starting material measured by HPLC b Identified and quantified by amino acid analysis c Ratio of measured % yield of glycin¢ to % photolysis of starting material
Given the partial success of the sacrificial carboxylate strategy, we considered whether two carboxylat¢
groups flanking the sulfonamide would achieve further improvement and set out to synthesise the two
disubstituted sulfonamides 12 and 13. In the event, synthesis of these highly functionalised 1,2,3-trisubstituted
benzcnes required some innovation, so the results described below may have wider application. The successful
syntheses of 12 and 13 were based on two pivotal reactions: the use of directed ortho-metalation ~° to achieve
the required 1,2,3-substitution pattern and then the convenient preparation of sulfonyl chlorides by two-phase
oxidation of sulfinates with N C S . 7
~ [~ CO2H 12 ~ OCH2CO2H 13
SO2NHCH2CO2H T "SO2NHCH2CO2H OCH2CO2H OCHzCO2H
Synthesis of 12 (Scheme 3) began with tert-butyl lithium-TMEDA metalation of the N,N-diisopropyl-
benzamide 14a, followed by quenching with sulfur dioxide. Oxidation of the crude sulfinate gave the
crystalline sulfonyl chloride 15a, from which the sulfonamide 16a was readily obtained. Hydrogenolysis of the
benzyl ether and alkylation of the derived phenol 17a smoothly gave the fully-prutected derivative 18a but we
could not hydrolyse the diisopropyl amide under any conditions that did not cause gross degradation. The
problem of this difficult hydrolysis has been recognised as a drawback of the directed ortho-metalation
G. Papageorgiou, J. E. T. Corrie / Tetrahedron 55 (1999)237-254 241
strategy as applied to N,N-dialkylbenzamides. ~° However, O-alkylation of amides with a trialkyloxonium
fluoroborate followed by acidic or alkaline hydrolysis has been used in other contexts to effect amide
cleavage. H In model studies, we found the N,N-diisopropylbenzamide 14== was unreactive towards Et3OBFo
but with the same reagent the diethylamide 14b was -50% converted to the corresponding ethyl ester (after
acidic hydrolysis). Therefore the sequence of Scheme 3 was repeated in the N,N-diethyl (b) series, and
treatment of 18b with Et3OBF 4 followed by aqueous H2SO 4 gave the benzisothiazolone 19 in 91% yield.
0 o 0 ~ N R 2 i'ii'iii ~, ~ NR2 iv'v = ~ N R 2
/
14a R = i-Pr 15a R = i-Pr i / 16a R =/-Pr, R 1 = Bn t4b R = E t 15b R = E t v / 16b R=Et , R l = B n , / / 17a R=/-Pr, R I = H
O O 17b R=Et , R1 = H
~ s N 2 % o 2 H ~ vii' vi i i ~ N R 2 "SO2NHCH2CO2Me
OCH2CO2H OCH2CO2 R1 19 18a R =/-Pr, R 1 = Et
18b R=Et , R 1=Me
Scheme 3: Reagents; i) t-BuLi-TMEDA; ii) $02; iii) NCS; iv) Methyl glycinate.HCI-NMM; v) H2-PdlC; vi) BrCH2CO2R-DIPEA; vii) Et3OBF4; viii) aq. H2SO 4
Cleavage of dialkylbenzamides assisted by the introduced ortho-substituent is a common feature of
directed ortho-metalation strategies ~° and the additional activation provided here by O-alkylation of the amide
may be useful in other applications of the method. In the present case the simultaneous hydrolysis of the two
ester groups elsewhere in the molecule was a convenient collateral benefit. Alkaline hydrolysis of 19 gave the
salt of the required compound 12, which was stable at neutral pH but slowly recyclised to 19 under even
mildly acidic conditions (pH <4). Thus the pure free acid form of 12 could not be isolated and its sodium salt
was generated as required without separation from inorganic salts (see Experimental).
For synthesis of diacid 13 (Scheme 4), directed ortho-metallation of 20a followed by SO 2 quench and
NCS oxidation cleanly gave the sulfonyl chloride 21a, which was converted to the N-sulfonylglycine ester
22a. Hydrogenolysis over Pd-C readily gave the resorcinol 23a but alkylation using BrCH2CO2Et-DIPEA
gave the O,N- and O,O-disubstituted compounds 24a and 24b, respectively, in an isolated ratio of 1.8:1. It
appeared that the first alkylation was at one of the phenolic groups but that the second occurred preferentially
at the sulfonamide nitrogen. To confirm this, one phenolic group was blocked by repeating the reaction
sequence with the benzyl methyl ether 20b, which ultimately gave the monomethoxysulfonamide 23b.
Treatment of this compound with BrCH2CO2Et-DIPEA gave the N- and O-alkylated products 24e and 24d,
242 G. Papageorgiou, J. E. T. Corrie / Tetrahedron 55 (1999) 237-254
respectively, in an isolated ratio of 3.6:1, thereby confirming the preferential N-alkylation. Relative
preferences for O- versus N-alkylation in these compounds are evidently finely balanced since under identical
conditions the phenolic sulfonamides 17a and 17b underwent only clean O-alkylation, as described above.
[~ OBn i, ii, iii ~ ~ . O B n
"SO2CI
OR OR
20a R = B n 21a R = B n 20b R = M e 2tb R = M e
[ ~ OR2
SO2NCH2CO2Me OR R 1
24a R-- H, R 1, R 2 = CH2CO2Et 24b R 1 = H, R, R 2 = CH2CO2Et 24c R = Me, R 1 = CH2CO2Et, R 2 = H 24d R = Me, R 1 = H, R 2 = CH2CO2Et 24e R, R 2 = CH2CO2Me, R 1 = PMB
vi
~ OBn
SO2NCH2CO2Me OR R 1
22a R = B n , R I = H 22b R = M e , R I = H 22c R = B n , R I = P M B
Iv SO2NCH2CO2Me
/ I OR R 1
23a R, R 1 = H 23b R = M e , R I = H 23c R = H , R 1 =PMB
Scheme 4: Reagents; i) n-BuLi-TMEDA; ii) SO2; iii) NCS; iv) MeO2CCH2NHR1-NMM; v) H2-Pd/C;
vi) BrCH2CO2R-DIPEA
In an attempt to prevent N-alkylation, 22a was N-acetylated (Ac20-NaOAc) to give 25, from which the
protecting benzyl groups were readily cleaved by hydrogenolysis. The ~H NMR spectrum of the crude product
confirmed structure 26. However, during attempted crystailisation the acetyl group underwent migration to one
of the adjacent phenolic oxygens to give a 1:4 mixture of the N- and O-acetyl compounds 26 and 27
respectively. The presence of the O-acetate was revealed by the appearance of new signals in the ]H NMR
spectrum, e.g. a triplet for the NH at 85.84 and a corresponding doublet for the adjacent methylene group at 8
3.84. The methoxy group of the ester also showed an upfield shift from 3.76 to 3.62 ppm. The ratio of the two
components was not changed by further heating (1 h reflux in MeCN), confirming that equilibration was
complete during the attempted crystallisation. N- to O-Migration of an acyl group is unusual under neutral or
mildly basic conditions but Ellman and co-workers have recently shown that deacylation of N-
acylsulfonamides can be activated by an N-cyanomethyl substituent. ~2 The N-methoxycarbonylmethyl
substituent in 26 has a similar activating effect and the presence of the phenolic groups as suitably sited
internal nucleophiles establishes a favorable situation for acyl migration.
~ OR I
SO2NCH2CO2Me I
O R 2 R 3
25 R 1, R 2 = Bn, R 3 = Ac 26 R 1, R 2 = H, R 3 = Ac 27 R ~, R 3 = H, R 2 = Ac
[~ OCH2COzMe
SO2NHCH2CO2Me OCH2CO2Me
28
G. Papageorgiou, J. E. T. Corrie / Tetrahedron 55 (1999) 237-254 243
The undesired N-alkylation of 23a was eventually blocked by protecting the nitrogen as its p-
methoxybenzyl derivative. Thus condensation of the sulfonyl chloride 21a with methyl N-(p-methoxy-
benzyl)glycinate and hydrogenolysis of the O-benzyl groups gave the resorcinol derivative 23e (Scheme 4).
No hydrogenolysis of the N-PMB substituent was observed under the conditions used. O-Alkylation of the two
phenolic groups with BrCH2CO2Me-DIPEA cleanly gave the triester 24e, from which the N-PMB group was
readily removed by CAN t3 to give 28. The required triacid 13 was then obtained by alkaline hydrolysis.
With the target compounds 12 and 13 in hand, their photolysis was examined under the same conditions
as for the monosubstituted compounds 2-4, and results are shown in Table 2. Disappointingly, the additional
carboxylate group in either of the disubstituted compounds had no additional effect on the fractional release of
free glycine from the starting compounds and the maximum conversion efficiency obtained with any of these
compounds is 30% for 2 (Table 1).
Table 2. Theoretical and actual product yields for photolysis of compounds 12 and 13
Compound Photolysis 11 % Photolysis a Glycine Yield Actual Yield c Time (min) Present ( % ) b Theoretical Yield
12 3 Yes 69.8 13.3 0.19 12 3 No 82.3 4.8 0.06 13 3 Yes 52.0 10.4 0.20 13 3 No 63.8 2.8 0.04
a Consumption of starting material measured by HPLC b Identified and quantified by amino acid analysis c Ratio of measured % yield of glycine to % photolysis of starting material
The failure of a second carboxylate group to have an incremental effect, taken together with the 5-7-fold
effect of a single carboxylate, suggests that pathways other than as shown in Scheme 1 must be considered for
photocleavage of these sulfonamides. At least two such routes may be considered to account for the 70-80% of
material that undergoes photolysis (i.e. disappearance of starting material as measured by HPLC) but does not
release gtycine. The first is that cleavage of the sulfonamide radical anion depicted in Scheme 1 may occur not
only as shown to produce a sulfonyl radical and an amine (the mechanism proposed by Hamada et al. 8) but
also in the opposite sense to give a sulfinate anion and an aminyl radical. Cleavage of sulfonamide radical
anions in this sense has been proposed by Simonet and co-workers '4 and confirmed by them in further work. 15
Formation of the aminyl radical (or its conjugate protonated amino radical cation) of a-amino acids is known
to result in decarboxylation ~6 and this process is unlikely to be intercepted by a carboxylate group on the
departing arenesulfinyl residue. Thus sulfonamide photocleavage mediated by single electron transfer probably
takes a dual course, one branch of which is inherently likely to result in destruction of a departing a-amino
acid. A second consideration is that all the compounds studied, with the exception of N-tosylglycine, were
244 G. Papageorgiou. J. E. T. Corrie /Tetrahedron 55 (1999) 237254
consumed to a similar extent upon irradiation whether or not the naphthalene 11 was present. Direct excitation
is possible because of spectral overlap of the chromophores of the various compounds with the transmission
band of the filter used in the irradiations. Notably those compounds with one or two oxygen substituents on
the aromatic ring, i.e. 4, 12 and 13, that have more intense chromophores overlapping to a greater extent with
the irradiating light, undergo more extensive direct photolysis. In all cases the yield of glycine from direct
photolysis was substantially lower than from photolysis in the presence of the naphthalene 11, both in absolute
terms and as a fraction of the converted starting material. Arenesulfonamides are known to undergo homolytic
photocleavage upon direct irradiation ~7 and this would be expected to lead to efficient decarboxylation for the
same reason as discussed above.
To determine whether the problems encountered above were specific to a-amino acids, photolysis of
compounds 29 and 30 derived from y-aminobutyric acid was examined in the presence of naphthalene 11. The
ratios of actual to theoretical photolysis yields of GABA were 0.17 and 0.34 for 29 and 30 respectively. The
higher release of intact amino acid from N-tosylGABA 29 than from N-tosylglycine is consistent with our
previous observation 7 that [3-alanine was released more efficiently than glycine, i.e, a carboxylate group further
from the a-position of the amino acid apparently suffers less decarboxylation during photocleavage. Even so,
the presence of a carboxyl group ortho to the sulfonamide as in 30 results in a 2-fold increase in the efficiency
of GABA release but nevertheless, 66% of 30 undergoes photolysis without releasing intact GABA.
The results described above clearly demonstrate that pathways other than the intended sulfonamide
cleavage are available for photodecomposition of these sulfonamides. The present data and those of other
workers 1+'~5 strongly suggest that cleavage of sulfonamide radical anions can occur by heterolysis, as shown in
Scheme 1, or by homolysis to generate a sulfinate and an aminyl radical. In addition, for the particular case of
compounds studied here, photodecarboxylation TM of the phenylacetic or phenoxyacetic acid side chains,
whether by direct or sensitised irradiation, may consume the compounds without necessarily leading to glycine
release. Although we have not sought fully to define the photolysis products of the various sulfonamides
described, the results show that these reagents cannot provide an effective means for photorelease of a-amino
acids. Even in the most favorable case (compound 2) the fraction of converted starting material that yields free
glycine is only 30% and the remaining proportion seems likely to decompose by way of reactive species that
could be significantly damaging to biological samples. The results suggest that photocleavage of
arenesulfonamides may merit further study, particularly in view of continued interest in their use as
photocleavable protecting groups. +9 Furthermore, the efficient syntheses of sulfonyl chlorides bearing
relatively complex substituents as described here may have wider application.
G. Papageorgiou, J. E. T. Corrie /Tetrahedron 55 (1999) 237-254 245
EXPERIMENTAL
General Procedures. Microanalyses were carried out by MEDAC Ltd., Brunel University, Uxbridge, U.K.
Amino acid analyses were performed at the Department of Biochemistry, University of Cambridge using a Pharmacia AlphaPlus analyser with ninhydrin detection, tH NMR spectra were determined in CDC% with
tetramethylsilane as internal standard unless otherwise stated on JEOL FX9OQ or Bruker AM400 WB spectrometers. J values are given in Hz. Positive ion FAB mass spectra at high resolution were obtained on a VG ZAB-SE instrument and negative ion spectra at low resolution were obtained by nanoelectrospray on a
Thermoquest LCQ ion trap instrument. Merck 9385 silica gel was used for flash chromatography. Organic
extracts were dried over Na2SO 4 and solvents were evaporated under reduced pressure. Sodium or ammonium
phosphate buffer solutions were prepared from NaH2POa'2H20 or NH4H2PO 4 at the specified molarities in
water and adjusted to the required pH value with 2 M aq. NaOH. Anion exchange chromatography was
performed on a column of DEAE-cellulose (2.5 × 40 cm). Triethylammonium bicarbonate (TEAB) buffer for elution was prepared by bubbling CO2 into an ice-cold 1 M solution of triethylamine in water until the pH
stabilised at -7.4. Pooled column fractions were evaporated at -1 mmHg and freed from buffer salts by repeated evaporation with MeOH. For NMR spectroscopy, triethylammonium salts were converted into
sodium salts by treatment with Dowex 50 (Na form). HPLC data were obtained on Waters equipment using either a reversed phase column [Merck Lichrosphere RP8 column (Cat. No. 50832)] or an anion exchange column [Whatman Partisphere SAX column, (Cat. No. 4621-0505)]. UV detection was with a Waters 484
tunable wavelength detector at wavelengths given in Table 3. Details of mobile phases are also given in Table
3 and flow rates were 1.5 ml min -~ in all cases. The following compounds were prepared by established methods or minor variations thereof: 2, 20 3, 21 10, 22 29, 23 and 30. 24
2-Benzyloxy-5-methylbenzenesulfonyl chloride 6. A solution of 2-benzyloxy-5-methylbromobenzene 525 (2.77 g, 10 mmol) in dry E%O (50 ml) was cooled under nitrogen to -78 °C and treated with TMEDA (1.8 ml,
12 mmol) and 1.6 M n-BuLi in hexane (7.5 ml, 12 mmol). The solution was stirred at -78 °C for 1 h and
transferred with a PTFE cannula to a vigorously stirred solution of sulfur dioxide (5 ml) in dry Et20 (50 ml) at -78 °C. A white solid precipitated instantly and the mixture was kept at -78 °C for 15 min, then allowed to
warm to rt over 1 h. The solvent was evaporated and the residue was resuspended in dry Et20 and re-
evaporated, ~hen suspended in aq. sodium phosphate (500 mM, pH 6.0; 100 ml) and readjusted to pH 6.0. EtOAc (100 ml) was added and the flask was cooled in an ice bath. N-Chlorosuccinimide (4.00 g, 30 mmol) was added and the two-phase mixture was stirred vigorously for 1 h. The organic phase was separated and the aqueous phase was washed with EtOAc. The combined organic phases were washed with water, dried, and
evaporated. Flash chromatography [EtOAc-hexanes (1:9)] gave 6 as white crystals (2.19 g, 74%), mp 101 °C
(Et20-hexanes): IR (Nujol) 1365, 1260 cm~; ~H NMR (90 MHz) 67.76 (d, J2.2, 1H), 7.24-7.56 (m, 6H), 7.01
(d, J8.8, 1H), 5.30 (s, 2H), 2.34 (s, 3H). Calcd for C~4HI3C103S: C, 56.66; H, 4.42. Found: C, 56.59; H, 4.41.
Methyl N-(2-benzyloxy-5-methylbenzenesulfonyl)glycinate 7. Methyl glycinate hydrochloride (2.63 g, 21 mmol) and N-methylmorpholine (NMM) (4.25 g, 42 mmol) were added to a solution of 6 (2.08 g, 7 mmol) in MeCN (50 ml) under nitrogen and the mixture was re fluxed for 3 h. After cooling to rt the solvent was
evaporated and the residue was dissolved in CH2C12 (120 ml) and washed successively with 2 M aq. HC1,
saturated aq. NaI-ICO 3 and water, dried and evaporated. Flash chromatography [EtOAc-hexanes (3:7)] gave 7 as white crystals (1.68 g, 68%), mp 102-103 °C (EtOAc-hexanes): IR (Nujol) 3295, 1745, 1320, 1150 cm'~;
'H NMR (90 MHz) 67.68 (d, J 2.2, 1H), 7.16-7.56 (m, 6H), 6.94 (d, J 8.2, 1H), 5.46 (t, J 5.3, 1H), 5.21 (s, 2H), 3.74 (d, J 5.3, 2H), 3.57 (s, 3H), 2.31 (s, 3H). Calcd for CI7HIgNOsS: C, 58.44; H, 5.48; N, 4.01. Found: C, 58.67; H, 5.50; N, 4.00.
246 G. Papageorgiou, J. E. T. Corrie / Tetrahedron 55 (1999) 237-254
Methyl N-(2-hydroxy-5-methylbenzenesulfonyl)glycinate 8. A solution of 7 (1.13 g, 3.2 mmol) in EtOH (100 ml) was stirred with 10% Pd-C (0.2 g) under hydrogen (1 atm) until gas consumption ceased (~10 min). The solution was filtered through Celite and the filtrate was concentrated and re-evaporated from CHCI 3 to give 8 as a white solid (1.03 g, 94%), mp 127-129 °C (EtOAc-hexanes): IR (Nujol) 3345, 3285, 1740, 1295, 1135 cml; ~H NMR (90 MHz) 69.69 (s, 1H), 7.49 (d, J 1.8, 1H), 7.20 (dd, J8.3 and 1.8, 1H), 6.89 (d, J8.3, 1H), 6.60 (br t, J4.8, 1H), 3.74 (d, J 4.8, 2H), 3.63 (s, 3H), 2.28 (s, 3H). Calcd for Ct0H~3NOsS: C, 46.33; H, 5.05; N, 5.40. Found: C, 46.36; H, 5.33; N, 5.44.
Methyl N-[2-(ethoxycarbonylmethoxy)-5-methylbenzenesulfonyl]glycinate 9. A solution of 8 (389 mg, 1.5 mmol), DIPEA (388 mg, 3 mmol) and ethyl bromoacetate (501 rag, 3 mmol) in dry MeCN (30 ml) was refluxed for 17 h, cooled to rt and the solvent was evaporated. The residue was dissolved in Et~O (100 ml) and washed with 2 M aq. HCI and brine, dried and evaporated. Flash chromatography [EtOAc-hexanes (1:1)] gave 9 as white crystals (400 mg, 77%), mp 64-65 °C (Et20-hexanes): IR (Nujol) 3240, 1735, 1610, 1330, 1155 cm~; ~H NMR (90 MHz) 67.64 (d, J 1.8, 1H), 7.30 (dd, J8.3 and 1.8, 1H), 6.79 (d, J8.3, 1H), 6.64-6.88 (m, 2H), 4.76 (s, 2H), 4.30 (q, J 7.5, 2H), 3.84 (d, d 5.7, 2H), 3.53 (s, 3H), 2.33 (s, 3H), 1.72 (t, J 7.5, 3H). Caled for Cj4HjgNOTS: C, 48.69; H, 5.54, N, 4.05. Found: C, 48.72; H, 5.52; N, 4.04.
N-[2-(Carboxymethoxy)-5-methylbenzenesulfonyl]glycine 4. A solution of 9 (363 mg, 1.05 mmol) in 0.2 M methanolic NaOH (10 ml) was refluxed for 2 h, acidified with conc. HCI, saturated with NaCI and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give 4 as white crystals (273 mg, 86%), mp 154-156 °C (acetone-hexanes): UV (EtOH) 2~Jnm 287 (dM'~cm l 2900); UV (25 mM ammonium phosphate, pH 7) 2,,~x/nm 290 (dM~cm ~ 3280); IR ('Nujol) 3180 br, 1740, 1720, 1325, 1140 cm~; 1H NMR (400 MHz) 6 7.65 (d, d 1.9, 1H), 7.30 (dd, d 8 and 1.9, 1H), 7.02 (t, J 5.7, I H), 6.85 (d, d 8, 1H), 4.74 (s, 2H), 3.73 (d, d 5.7, 2H), 2.33 (s, 3H), 2.17 (s, 6H, acetone solvent): HRMS (FAB) m/z 304.0941 (M + H) + (CHHt3NO7S + H requires 304.1500). Calcd for CHH~3NOTS.Me2CO: C, 46.53; H, 5.30; N, 3.88. Found: C, 46.44; H, 4.97; N, 4.31.
1,5-Bis[3-(dihydroxyphosphoryloxy)propoxy]naphthalene 11. A solution of 2-methyl-2-butene (2 M in THF; 50.6 ml, 101.25 mmol) was cooled to 0 °C under nitrogen and treated with BH3.Me2S (10 M in THF; 4.5 ml, 45 mmol). The mixture was stirred at rt for 2 h, cooled in ice and a solution of 1,5- bis(allyloxy)naphthalene 26 (4.81 g, 20 mmol) in dry THF (50 ml) was added dropwise. After 5 min the ice bath was removed and the mixture was stirred at rt for 2.5 h. The solution was cooled in ice and sequentially treated with EtOH (25 ml), water (10 ml), 2 M aq. NaOH (15 ml) and 30% aq. H202 (10 ml), then refluxed for 1 h. After cooling to rt the solution was poured into water (100 ml) and extracted with CH2C12. The combined organic phases were washed with water, dried and evaporated to yield 1,5-bis(3-hydroxypropoxy)naphthalene as white crystals (2.94 g, 53%), mp 150-151 °C (EtOH); IR (Nujol) 3360, 3295 cm~; ~H NMR (90 MHz, DMSO-dr) 8 7.76 (d, J 8, 2H), 7.32 (t, J 8, 2H), 6.87 (d, J 8, 2H), 4.41 (t, J 5, 2H, exchanged with D20 ), 4.23 (t, J6 , 4H), 3.81 (t after D20 exchange, J6, 4H), 2.09 (quintet, J6, 4H). Calcd for C16H2004: C, 69.54; H, 7.30. Found: C, 69.69; H, 7.48.
1H-Tetrazole (314 mg, 4.5 mmol) was added under nitrogen to a stirred solution of 1,5-bis(3- hydroxypropoxy)naphthalene (276 mg, 1 mmol) and bis-(2-cyanoethyl) N,N-diisopropylphosphoramidite 27 (678 mg, 2.5 mmol) in dry THF (40 ml). After 4 h at rt the mixture was cooled in an ice bath and treated dropwise over 5 min with a solution of ra-chloroperbenzoic acid (55% peracid; 1.04 g, 3.3 mmol) in CH2C12 (10 ml). The solution was stirred at 4 °C for 1 h then diluted with CH2CI 2 (40 ml) and washed with 10% aq. Na2S205. The organic phase was separated and the aqueous phase was re-extracted with CHCI 3. The combined organic phases were washed successively with 1 M aq. HC1, saturated aq. NaHCO 3 and brine, dried and
G. Papageorgiou, J. E. T. Corrie /Tetrahedron 55 (1999)237-254 247
evaporated under reduced pressure. Flash chromatography [MeOH-EtOAc (3:7)] gave 1,5-bis{3-[bis(2- cyanoethoxy)phosphoryloxy]propoxy}naphthalene as a white solid (302 mg, 47%), mp 74-75 °C (aq. EtOH); IR (Nujol) 2250, 1270 cm~; ~H NMR (90 MHz) 87.82 (d, J 8, 2H), 7.37 (t, J8 , 2H), 6.86 (d, J 8 H, 2H), 3.96- 4.64 (m, 16H), 2.61 (t, J6 , 8H), 2.32 (quintet, J6 , 4H). Calcd for CzsH34N4OtoP2: C, 51.86; H, 5.28; N, 8.63. Found: C, 51.79; H, 5.34; N, 8.39.
A sample of the bis-phosphotriester (117 mg, 180 lamol) was dissolved in MeOH (27 ml) and 2 M aq. NaOH (3 ml) and kept at 50 °C for 1 h. The solution was concentrated under reduced pressure (-10 ml), diluted with water, adjusted to pH 7 with 1 M aq. HCI and washed with Et20. The aqueous solution was diluted with water to a conductivity of 800 ~tS cm" and purified by anion exchange chromatography using a linear gradient formed from 10 and 1000 mM TEAB (each 1000 ml). Fractions containing the product, which eluted at -195 mM TEAB, were processed as described above to afford 11 as its tetrakis(triethylammonium) salt (62 ~tmol, 34%); negative ion MS m/z 435 (M + 3H)- (Ct6HlsOt0P2+ 3H requires 435). The sodium salt had ~H NMR (400 MHz, D20, acetone ref.) 87.91 (d, J 8, 2H), 7.50 (t, J 8, 2H), 7.12 (d, J 8, 2H), 4.35 (t, J6, 4H), 4.07 (dt, J6, JH.P 6, 4H), 2.23 (quintet, J6 , 4H).
3-Benzyloxy-N,N-diisopropylbenzamide 14a. A solution of 3-benzyloxybenzoic acid 2s (11.41 g, 50 mmol) and SOC12 (7.3 ml, 100 mmol) in dry benzene (150 ml) was refluxed for 1 h. The solvent was evaporated, the residual oil was dissolved in dry benzene (150 ml) and treated with di-isopropylamine (35 ml, 250 mmol) and the mixture was refluxed for 0.75 h. The solvent was evaporated and the residue was dissolved in EhO and washed with 2 M aq. HC1, saturated aq. NaHCO 3 and brine, dried and evaporated to give 14a as white needles (13.6 g, 87%), mp 86-87 °C (hexanes): IR (Nujol) 1620 cm~; ~H NMR (90 MHz) 87.16-7.52 (m, 6H), 6.80- 7.04 (m, 3H), 5.06 (s, 2H), 3.32-3.92 (m, 2H), 0.8-1.60 (m, 12H). Calcd for C20H25NO2: C, 77.14; H, 8.09, N, 4.50. Found: C, 77.08; H, 8.19; N, 4.51.
3-Benzyloxy-N,N-diethylbenzamide 14b. Prepared as for 14a as a pale viscous oil (22.58 g, 100%) which was used without further purification; IR (film) 1630 cm'~; ~H NMR (90 MHz) 8 7.06-7.44 (m, 6H), 6.76-7.04 (m, 3H), 5.04 (s, 2H), 2.80-3.72 (m, 4H), 0.72-1.32 (m, 6H).
2-Benzyloxy-6-(N,N-diisopropylcarbamyl)benzenesulfonyl chloride 15a. Prepared as for l$b, white crystals (68%), mp 161 °C (EtOAc-hexanes): IR (Nujol) 1640, 1350 cm~; ~H NMR (400 MHz) 87.60 (dd, d 7.6 and 0.7, 2H), 7.53 (dd, J8.5 and 7.5, 1H), 7.39-7.43 (m, 3H), 7.11 (dd, J 8.5 and 0.9, 1H), 6.84 (dd, d 7.5 and 0.9, 1H), 5.35 (s, 2H), 3.58 (septet, J6.7, 1H), 3.52 (septet, J6.7, 1H), 1.56 (d, J6.8, 3H), 1.53 (d, J6.8, 3H), 1.24 (d, J 6.8, 3H), 1.07(d, d 6.8, 3H). Calcd for C20H24CINO4S: C, 58.60; H, 5.90; N, 3.42. Found: C, 58.57; H, 5.91; N, 3.44.
2-Benzyloxy-6-(N,N-diethylcarbamyl)benzenesulfonyl chloride 15b. A solution of 14b (3.07 g, 10.8 mmol) in dry Et20 (100 ml) was cooled under nitrogen to -78 °C and treated with TMEDA (1.96 ml, 13 mmol) and 1.7 M tert-BuLi in hexane (7.6 ml, 13 mmol). After 1 h at -78 °C the solution was transferred with a PTFE cannula to a vigorously stirred solution of SO2 (5 ml) in dry Et20 (50 ml) at -78 °C. A white solid precipitated instantly and the mixture was kept at -78 °C for 15 min, then allowed to warm to rt over 1 h. The solvent was evaporated and the residue was resuspended in dry EtzO and re-evaporated. The residual solid was oxidised with NCS (4.32 g, 32.4 mmol) as described for preparation of compound 6. Flash chromatography [EtOAc-hexanes (1:1)] gave 15b as white crystals (1.77 g, 47%), mp 111-113 °C (EtOAc-hexanes): IR (Nujol) 1645, 1370, 1175 cm"; ~H NMR (400 MHz) 67.61 (dd, J 8.5 and 7.5, 1H), 7.52 (dd, J 7.2 and 1.3, 2H), 7.41 (t, J 7.2, 2H), 7.34 (tt, J 7.2 and 1.3, 1H), 7.14 (dd, J 8.5 and 0.9, 1H), 6.90 (dd, J 7.5 and 0.9, 1H), 5.36 (s, 2H), 3.77 (dq, J 14 and 7, 1H), 3.34 (dq, J 14 and 7, 1H), 3.10-3.24 (m, 2H), 1.25 (t, J7 , 3H), 1.08 (t,
248 G. Papageorgiou, J. E. T. Corrie /Tetrahedron 55 (1999) 237-254
J7, 3H). Calcd for C~sH20CINO4S: C, 56.62; H, 5.28; N, 3.67. Found: C, 56.81; H, 5.22; N, 3.64.
Methyl N-[2-benzyloxy-6-(N,N-diisopropylcarbamyl)benzenesulfonyl]glycinate 16a. Prepared as for 16b, white crystals (83%), mp 138-139°C (EtOAc-hexanes): IR (Nujol) 3170, 1740, 1615, 1340, 1150 cm't; ~H NMR (400 MHz) 87.56 (dd, J8.1 and 0.8, 2H), 7.45 (t, J7.8, 1H), 7.34-7.43 (m, 3H), 7.05 (dd, J8.1 and 0.8, 1H), 6.81 (dd, J 7.5 and 0.8, 1H), 5.65 (t, J 5.2, 1H), 5,28 and 5.24 (ABq, J 17.2, 2H), 4.02 (dd, J 18.2 and 5.6, 1H), 3.84 (dd, J 18.2 and 4.9, I H), 3.67 (septet, J 6.8, 1H), 3.49 (septet, J 6.8, 1H), 3.58 (s, 3H), 1.56 (d, J 6.8, 3H), 1.52 (d, J6.8, 3H), 1.24 (d, J6.8, 3H), 1.06 (d, J6.8, 3H). Calcd for C23H30N206S: C, 59.72; H, 6.54; N, 6.05. Found: C, 59.69; H, 6.60; N, 5.97.
Methyl N-[2-benzyloxy-6-(N,N-diethylcarbamyl)benzenesulfonyl]glycinate 16b. A solution of the sulfonyl chloride 15h (5.73 g, 15 mmol) in MeCN (150 ml) was treated with methyl glycinate hydroehloride (5.64 g, 45 mmol) and NMM (9.9 ml 9.11 g, 90 mmol) as described above for preparation of 7. Flash chromatography [EtOAc-hexanes (4:1)] gave 16b as white crystals (4.55 g, 70%), mp 94-95 °C (EtOAc-hexanes): IR (Nujol) 3140br, 1740, 1375, 1155 cm~; ~H NMR (400 MHz) 8 7.55 (dd, J 8. I and 1.4, 2H), 7.50 (dd, J 8.1 and 7.5, 1H), 7.42 (t, J7.2, 2H), 7.36 (tt, J7.2 and 1.3, 1H), 7.08 (dd, J8.1 and 0.9, 1H), 6.86 (dd, J7.5 and 0.9, IH), 5.66 (t, J5.5, 1H), 5.25 and 5.30 (ABq, J 17.3, 2H), 3.99 (dd, J 18.3 and 5.5, 1H), 3.85 (dd, J 18.3 and 5.5, 1H), 3.70 (dq, J 14 and 7, 1H), 3.58 (s, 3H), 3.37 (dq, J 14 and 7, 1H), 3.20 (q, J 7, 2H), 1.26 (t, J7, 3H), 1.08 (t, J7, 3H). Caled for C2jH26N2068: C, 58.05; H, 6.03; N, 6.44. Found: C, 57.82; H, 6.00; N, 6.41.
Methyl N-[2-hydroxy-6-(N,N-diisopropylcarbamyl)benzenesulfonyl]glycinate 17a. Prepared as for 17b, (71%), mp 72-73 °C (EtOAc-hexanes): IR (Nujol) 3280, 1765, 1750, 1355, 1155 cm~; JH NMR (400 MHz) 6 9.45 (s, 1H), 7.42 (t, J7.9, ill), 7.01 (dd, J8.6 and 1.0, 1H), 6.75 (dd, J 1.0 and 7.5, 1H), 6.60 (t, J5.7, 1H), 3.90 (dd, J 17.4 and 6.7, 1H), 3.74 (dd, J 17.4 and 5.0, 1H), 3.71 (septet, J6.6, 1H), 3.65 (s, 3H), 3.51 (septet, J6.6, IH), 1.57 (d, J6.6, 3H), 1.50 (d, J6.6, 3H), 1.20 (d, J6.6, 3H), 1.14 (d, J6.6, 3H). HRMS (FAB) m/z 373.1426 (M + H) + (CI6H24N206S + H requires 373.1433).
Methyl N-[2-hydroxy-6-(N,N-diethylcarbamyl)benzenesulfonyl]glycinate 17b. Compound 16b (4.15 g, 9.5 mmol) was debenzylated as described above for preparation of 8 to give 17b as a crystalline solid (2.69 g, 82%), mp 77-78 °C (EtOAc-hexanes): IR (Nujol) 3245, 1765, 1155 cmJ; 1H NMR (400 MHz) 69.44 (s, 1H, exchanged with D20), 7.44 (dd, J 8.5 and 7.3, IH), 7.04 (dd, J8.5 and 1, IH), 6.81 (dd, J7.3 and 1, 1H), 6.56 (t, J 5.6, 1H), 3.92 (dq, J 17.2 and 6.7, 1H), 3.75 (dq, J 17.2 and 4.9, IH), 3.65 (dq, J 14 and 7, 1H), 3.66 (s, 3H), 3.43 (dq, J 14 and 7, 1H), 3.15-3.27 (m, 2H), 1.25 (t, J7, 3H), 1.13 (t, J7 , 3H). Caled for C~4H20N20~S: C, 48.83; H, 5.85; N, 8.13. Found: C, 48.87; H, 5.90; N, 7.90.
Methyl N-[2-(eth•xycarb•ny•meth•xy)-6-(N•N-diis•pr•py•carbamy•)benzenesu•f•nyl]g•ycinate 18a. A solution of 17a (1.12 g, 3 mmol) in dry MeCN (90 ml) was treated with DIPEA (1.05 ml, 6 retool) and ethyl bromoacetate (0.67 ml, 6 mmol) and the mixture was refluxed for 16 h. The solvent was evaporated and the residue was dissolved in Et20 (100 ml) and washed with 2 M aq. HCI and brine, dried and evaporated. Flash chromatography [EtOAc-hexanes (7:3)] gave 18a as white crystals (919 rag, 67%), mp 95-97 °C (EtOAc- hexanes): IR (Nujol) 3210, 1755, 1735, 1630, 1340, 1160 cm~; ~H NMR (400 MHz) 67.48 (t, d8.0, 1H), 7.04 (t, J5.4, 1H), 6.88 (d, J 8.0, 1H), 6.85 (d, J 8.0, IH), 4.83 and 4.77 (ABq, J 14.9, 2H), 4.32 (q, J7.3, 2H), 4.05 (dd, J 18.4 and 6.7, 1H), 3.91 (dd, J 18.4 and 4.4, 1H), 3.61 (septet, J6.7, 1H), 3.52 (s, 3H), 3.48 (septet, J6.7, 1H), 1.56 (d, J6.7, 3H), 1.52 (d, J6.7, 3H), 1.33 (t, J 7.3, 3H), 1.23 (d, J6.7, 3H), 1.04 (d, J6.7, 31-1). Caled for C20H30N2OsS: C, 52.39; H, 6.59, N, 6.11. Found: C, 52.43; H, 6.66; N, 6.09.
G. Papageorgiou. J. E. T. Corrie /Tetrahedron 55 (1999) 237-254 249
Methyl N-[2-(methoxycarbonylmethoxy)-6-(N,N-diethylcarbamyl)benzenesulfonyl]glycinate 18b. A solution of 17b (2.41 g, 7 mmol), DIPEA (1.8 ml, 14 mmol) and methyl bromoacetate (1.33 ml, 14 mmol) in dry MeCN (210 ml) was treated as described for preparation of 18a. Flash chromatography (EtOAc) gave 18b
as white crystals (2.31 g, 79%), mp 41-43 °C (CH2C12-hexanes): IR (Nujol) 3150br, 1765, 1740, 1615, 1155 cm~; ~H NMR (400 MHz) 67.50 (t, J 8, 1H), 7.05 (dd, J6.8 and 4.4, 1H), 6.92 (dd, J8 .2 and l, 1H), 6.90 (dd, d7.4 and l, 1H), 5.30 (s, 1H, 0.5 CHzC12 solvent), 4.86 and 4.79 (ABq, J 14.9, 2H), 4.04 (dd, J 18.5 and 6.8, lH), 3.89 (dd, J 18.5 and 4.4, 1H), 3.84 (s, 3H), 3.73 (dq, J 14 and 7, 1H), 3.52 (s, 3H), 3.34 (dq, J 14 and 7, 1H), 3.16 (q, d7, 2H), 1.24 (t, J 7 , 3H), 1.04 (t, d7, 3H). Calcd for C,TH24N2OsS-V2CH2Clz: C, 45.80; H, 5.49, N, 6.10. Found: C, 45.95; H, 5.36; N, 6.10.
2-Carboxymethyl-7-carboxymethoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide 19. A solution of 18b (833 mg, 1.8 mmol) in dry CH2C12 (15 ml) was treated with triethyloxonium tetrafluoroborate (1 M solution in CH2C12, 10 ml, 10 mmol) and the mixture stirred at rt for 22 h. The solvent was evaporated and the residue was dissolved in 0.5 M aq. H2SO 4 and refluxed for 1 h, then diluted with water, saturated with NaC1 and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give a solid which was washed with chloroform to give 19 as white crystals (519 mg, 91%), mp 250-252 °C (acetone-hexanes): UV (EtOH) 2,,ax/nm 304 (e/M~cm -~ 3740), UV [EtOH-water (1:4)] /%max/nnl 308 (e/M~cm "1 4000); IR (Nujol) 1750, 1730 cm-~; 'H NMR (400 MHz, DMSO-d6) 67.93 (t, J 8, 1H), 7.67 (d, J 7.5, 1H), 7.61 (d, d 8.6, 1H), 5.09 (s, 2H), 4.44 (s, 2H). HRMS (FAB) m/z 337.9930 (M + H) + (CI~HgNORS+ H requires 337.9947). Calcd for CHHgNOsS: C, 41.91; H, 2.88; N, 4.44. Found: C, 41.71; H, 2.96; N, 4.30. The sodium salt had ~H NMR (400 MHz, D20, acetone ref.) 67.89 (dd, J8.5 and 7.5, 1H), 7.67 (d, J7.5, 1H), 7.38 (d, J8.5, 1H), 4.76 (s, 2H), 4.29 (s, 2H).
N-[(2-Carboxy-6-carboxymethoxy)benzenesulfonyl]glycinate 12. A solution of 19 (0.5 g, 1.58 mmol) in 2.5 M aq. NaOH (20 ml) was refluxed for 3 h. The progress of the reaction was followed by anion exchange HPLC (see Table 3 for retention times). The solution was diluted with water, adjusted to pH 7.6 with 1 M aq. HCI and washed with E%O. The aqueous solution was diluted with water to a conductivity of 2500 ~tS cm ~ and purified by anion exchange chromatography using a linear gradient formed from 10 and 400 mM TEAB (each 1000 ml). Fractions containing the product, which eluted at - 160 mM TEAB, were processed as described above to afford 12 as its tris(triethylammonium) salt (1.26 mmol, 80%). UV (50 mM Na phosphate, pH 7.0) 2~,x/nm 287 (e/M~cm ~ 4000); negative ion MS m/z 332 (M + 2H)- (CIIHsNOgS+ 2H requires 332). tH NMR (sodium salt) (400 MHz, D20, acetone ref.) 67.59 (dd, J8.3 and 7.6, 1H), 7.00 (dd, J0 .8 and 8.3, 1H), 6.96 (dd, J0.9 and 7.6, 1H), 4.66 (s, 2H), 3.46 (s, 2H).
On storage the triethylammonium salt slowly recyclised to 19, and a pure sample for photolysis was prepared by hydrolysis of 19 (18 mg, 57 p.mol) in 0.25 M aq. NaOH (2 ml) under reflux for 2 h, when HPLC analysis (see Table 3) showed that hydrolysis was complete. The solution was diluted to 25 ml with 25 mM ammonium phosphate, pH 7 and the pH was readjusted to 7 to give a solution of 12 (2.28 mM) which was used to prepare solutions for photolysis as described below.
2, 6-Bis(benzyloxy)benzenesulfonyl chloride 21a. A solution of resorcinol dibenzyl ether 29 20a (7.26 g, 25 mmol) in dry Et20 (200 ml) was cooled to 0 °C and treated with TMEDA (4.52 ml, 30 mmol) and 1.6 M n- BuLi in hexane (18.75 ml, 30 mmol) After 1 h at 0 °C the solution was transferred with a PTFE cannula to a solution at -78 °C of SO2 (10 ml) in dry Et20 (50 ml). The mixture was kept at -78 °C for 15 min and allowed to warm to rt over 1 h. The solvent was evaporated and the residue was resuspended in dry Et20 and re- evaporated. The crude sulfinate salt was oxidised with NCS as described for preparation of 6 and the product was flash chromatographed [EtOAc-hexanes (3:7)] to give 21a as white crystals (6.01 g, 62%), mp 95-96 °C
250 G. Papageorgiou, J. E. T. Corrie / Tetrahedron 55 (1999) 237-254
(EhO-hexanes): IR (Nujol) 1370, 1250 cm-~; ~H NMR (90 MHz) 6 7.20-7.60 (m, 11H), 6.66 (d, J 8.3, 2H), 5.24 (s, 4H). Calcd for C20HI7C104S: C, 61.77; H, 4.41. Found: C, 61.91; H, 4.41.
2-Benzyloxy-6-methoxybenzenesulfonyl chloride 2lb. Prepared as for 21a from 3-benzyloxyanisole 20b, 3° white crystals (75%), mp 101-102 °C (Et20-hexanes): IR (Nujol) 1365, 1170 cm~; ~H NMR 6(90 MHz) 7.24- 7.60 (m, 6H), 6.66 (d, J 9, 1H), 6.63 (d, J 9 Hz, 1H), 5.25 (s, 2H), 3.96 (s, 3H). Calcd for Cj4HI3C104S: C, 53.76; H, 4.19. Found: C, 53.83; H, 4.19.
Methyl N-(2,6-dibenzylox?'benzenesulfonyl)glycinate 22a. A mixture of 21a (4.67 g, 12 mmol), methyl glycinate hydrochloride (3.01 g, 24 mmol) and NMM (4.85 g, 48 mmol) in MeCN (120 ml) was treated as described for preparation of 7. Flash chromatography [EtOAc-hexanes (2:3)] gave 22a as white crystals (4.13 g, 78%), mp 70-71 °C (EtOAc-hexanes): IR (Nujol)3275, 1745, 1360, 1245, 1170 cm'~; ~H NMR (90 MHz) 7.20-7.60 (m, 11H), 6.67 (d, J8.8, 2H), 5.84 (t, J5.6, 1H), 5.19 (s, 4H), 3.83 (d, J5.6, 2H), 3.54 (s, 3H). Calcd for Cz3Hz3NO68: C, 62.57; H, 5.52; N, 3.17. Found: C, 62.79; H, 4.95; N, 3.17.
Methyl N-(2-benzyloxy-6-methoxybenzenesulfonyl)glycinate 22b. Prepared as described for 22a, colourless viscous oil (75%); IR 3340, 1740, 1345, 1160 cmt; ~H NMR 6(90 MHz) 7.20-7.56 (m, 6H), 6.64 (d, J 8, 1H), 6.60 (d, J 8, I H), 5.88 (t, J 6, 1H), 5.18 (s, 2H), 3.92 (s, 3H), 3.80 (d, J 6, 2H), 3.58 (s, 3H).
Methyl N-(4-methoxybenzyl)glycinate. A mixture ofp-anisaldehyde (6.81 g, 50 mmol), methyl glycinate hydrocb.loride (6.28 g, 50 mmol) and EhN (6.97 ml, 50 mmol) in benzene (50 ml) was refluxed for 7 h using a Dean-Stark trap. The solution was washed with water and the organic phase was dried and evaporated to give a pale yellow oil which crystallised on standing under vacuum. Recrystallisation (Et20-hexanes) gave methyl N-(4-methoxybenzylidene)glycinate as white crystals (8.44 g, 81%), mp 69-70 °C: IR (Nujol) 1745, 1650 cm]; 'H NMR (90 MHz) 68.20 (s, 1H), 7.70 (d, J9, 2H), 6.90 (d, J9, 2H), 4.37 (s, 2H), 3.83 (s, 3H), 3.76 (s, 3H). Calcd for C,Hj3NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.90; H, 6.28; N, 6.68.
A solution of the imine (8.37 g, 40 mmol) in MeOH (50 ml) was cooled in an ice bath and treated portionwise with NaBH4 (3.78 g, 100 mmol). The mixture was stirred for 1 h at rt, concentrated in vacuo and the residue was mixed with water and extracted with EtzO. The organic phase was dried, evaporated and fractionally distilled to give the title ester as a colourless oil (5.53 g, 62%), bp 114-120 °C/0.5 mmHg: IR (film) 3330, 1740 cm-~; 1H NMR (400 MHz) 67.23-7.26 (m, 2H), 6.84-6.87 (m, 2H), 3.79 (s, 3H), 3.73 (s, 2H), 3.72 (s, 3H), 3.40 (s, 2H), 2.01 (br s, 1H).
Methyl N-(2, 6-dibenzyloxybenzenesulfonyl)-N-(4-methoxybenzyOglycinate 22e. A mixture of the sulfonyl chloride 21a (6.04 g, 15.5 mmol), methyl N-(4-methoxybenzyl)glycinate (4.45 g, 21.3 mmol) and NMM (2.75 ml, 25 mmol) in MeCN (120 ml) was treated as described above for preparation of 7. Flash chromatography [EtOAc-hexanes (3:7)] gave 22e as white crystals (7.53 g, 81%), mp 75-77 °C (EtOAc-hexanes): IR (Nujol) 1755, 1345, 1160 cm]; ~H NMR (90 MHz) 67.16-7.64 (m, 11H), 7.03 (d, J9, 2H), 6.56-6.88 (m, 4H), 5.14 (s, 4H), 4.38 (s, 2H), 3.76 (s, 5H), 3.42 (s, 3H). Calcd for C31H3~NO7S: C, 66.29; H, 5.56; N, 2.49. Found: C, 66.27; H, 5.53; N, 2.54.
Methyl N-(2,6-dihydroxybenzenesulfonyl)glycinate 23a. Compound 22a (2.43 g, 5.5 mmol) was debenzylated as described above for 8 to give 23a as a white solid (1.4 g, 79%), mp 148-150 °C (EtOAc- hexanes): IR (Nujol) 3330, 3290, 1725, 1610, 1130 cmt; ~H NMR (90 MHz, CDCI3-DMSO-d6) 67.24 (t, JS, 1H), 6.45 (d, J8, 2H), 3.79 (s, 2H), 3.65 (s, 3H). Calcd for CgHI]NO6S: C, 41.38; H, 4.24; N, 5.36. Found: C, 41.42; H, 4.34; N, 5.33.
G. Papageorgiou, J. E. T. Corrie / Tetrahedron 55 (1999) 237-254 251
Methyl N-(2-hydroxy-6-methoxybenzenesulfonyl)glycinate 23b. Prepared as described for 23a, eolourless viscous oil (73%); IR 3390, 1745, 1225, 1130 cm~; tH NMR 6(90 MHz) 9.56 (s, 1H), 7.36 (t, JS, 1H), 6.60 (d, J 8, 1H), 6.48 (d, J6.6, 1H), 5.82 (t, d5, 1H), 5.18 (s, 2H), 3.92 (s, 3H), 3.78 (d, J5, 2H), 3.64 (s, 3H).
Alkylation of23a. A solution of 23a (261 mg, 1 mmol), DIPEA (0.7 ml, 4 mmol) and ethyl bromoaeetal¢ (0.44 ml, 4 mmol) in dry MeCN (20 ml) was refluxed for 18 h. Two products were isolated after the workup procedure described for 9 and flash chromatography [EtOAc-hexanes (1:1)]. The major product was methyl N-(2-eth•xycarb•ny•meth•xy-6-hydr•xybenzenesu•f•ny•)-N-(eth•xycarb•ny•methy•)g•ycinate 24a (229 mg, 53%), mp 144-146 °C (Et20-hexanes): IR (Nujol) 3270, 1765, 1745, 1325, 1130 cml; IH NMR (400 MHz) 6 9.86 (s, 1H), 7.31 (t, J 8.2, 1H), 6.63 (d, J 8.9, 1H) 6.33 (d, J 7.8, 1H), 4.63 (s, 2H), 4.36 (s, 2H), 4.30 (s, 2H), 4.28 (q, J 7.2, 2H), 4.08 (q, J 7.2, 2H), 3.65 (s, 3H), 1.32 (t, J 7.2, 3H), 1.19 (t, J 7.2, 3H). Caled for CITH23NO~0S: C, 47.11; H, 5.35, N, 3.23. Found: C, 46.86; H, 5.30; N, 3.33.
The minor product was methyl N-[2,6-bis(ethoxycarbonylmethoxy)benzenesulfonyl]glycinate 24b, colourless oil (124 mg, 29%): ~H NMR (90 MHz) 67.20-7.44 (m, 2H), 6.60 (d, J 8, 2H), 4.74 (s, 4H), 4.26 (q, J7.5, 2H), 3.94 (d, J6, 2H), 3.53 (s, 3H), 1.28 (t, J7.5, 3H).
Alkylation of23b. A mixture of the phenol 23b (826 mg, 3 mmol), DIPEA (775 mg, 6 mmol) and ethyl bromoacetate (1.00 g, 6 mmol) was treated as described for compound 18a. Flash chromatography [EtOAc- hexanes (1:1)] gave two major products. The less polar product was methyl N-(2-hydroxy-6-methoxy- benzenesulfonyl)-N-(ethoxycarbonylmethyl)glycinate 24e as white crystals (632 mg, 58%), mp 87-88 °C (EtOAc-hexanes): IR (Nujol) 3250, 1750, 1335, 1125 cml; ~H NMR 6(90 MHz) 9.76 (s, 1H), 7.32 (t, J 8, 1H), 6.56 (d, J 8, 1H), 6.40 (d, J 8, 1H), 4.31 (s, 2H), 4.29 (s, 2H), 4.08 (q, J 7.5, 2H), 3.87 (s, 3H), 3.66 (s, 3H), 1.21 (t, J 7.5, 3H). Calcd for C~4H~gNOsS'½EtOAc: C, 47.40; H, 5.72; N, 3.45. Found: C, 47.37; H, 5.41; N, 3.63. The more polar product was methyl N-(2-ethoxycarbonylmethoxy)-6-methoxybenzenesulfonyl- glycinate 24d (169 mg, 16%), mp 71-72 °C (EtOAc-hexanes): IR (Nujol) 3250, 1755, 1735, 1355, 1115 cm~; ~H NMR (90 MHz) 67.40 (t, J 8, 1H), 7.06 (t, J 6, 1H), 6.70 (d, J 8, IH), 6.52 (d, J 8, 1H), 4.75 (s, 2H), 4.28 (q, J 7.5, 2H), 3.92 (d, J 6.3, 2H), 3.87 (s, 3H), 3.56 (s, 3H), 1.31 (t, J 7.5, 3H). Calcd for Ct4H19NOsS: C, 46.53; H, 5.30, N, 3.87. Found: C, 46.47; H, 5.23; N, 3.87.
Methyl N-(2,6-dihydroxybenzenesulfonyl)-N-(4-methoxybenzyl)glycinate 23c. Compound 22e (6.89 g, 12.3 mmol) was debenzylated as described for 8 to give 23e as white needles (3.59 g, 77%), nap 131-132 *C (EtOAc-hexanes): IR (Nujol) 3320, 3220, 1125 cm'~;JH NMR (90 MHz) 6 8.64 (br s, 2H), 7.32 (t, J 8, 1H), 6.96-7.20 (m, 2H), 6.68-6.92 (m, 2H), 6.56 (d, J 8, 2H), 4.39 (s, 2H), 3.94 (s, 2H), 3.78 (s, 3H), 3.62 (s, 3H). Calcd for CITHI9NO7S: C, 53.54; H, 5.02; N, 3.67. Found: C, 53.43; H, 5.01; N, 3.64.
Methyl N-[2,6-bis(methoxycarbonylmethoxy)benzenesulfonyl]-N-(4-methoxybenzyl)glycinate 24e. A solution of 23e (1.91 g, 5 mmol), DIPEA (8.7 ml, 50 retool) and methyl bromoacetate (4.73 ml, 50 mmol) in dry MeCN (150 ml) was refluxed for 67 h. The solvent was evaporated and the residue was dissolved in MeOH (150 ml) and stirred at rt for 1.5 h with Et3N (10 ml). The solution was concentrated and the residue was mixed with 2 M aq. HCI and extracted with Et20. The combined organic phases were washed with brine, dried, evaporated and flash chromatographed [EtOAc-hexanes (3:2)] to give 24e as a light brown oil (2.48 g, 94%) which was used in the next step without further purification. IR (film) 1750, 1345, 1120 cm'l; IH NMR (90 MHz) 6 7.36 (t, J 7, 1H), 7.16 (d, J 8, 2H), 6.78 (d, J 8, 2H), 6.60 (d, J 7, 2H), 4.69 (s, 4H), 4.59 (s, 2H), 4.12 (s, 2H), 3.77 (s, 3H), 3.76 (s, 6H), 3.53 (s, 3H); HRMS (FAB) m/z 526.1403 (M + H) + (C23H27NOt~S + H requires 526.1383).
252 G. Papageorgiou, J. E. 7: Corrie / Tetrahedron 55 (1999) 237-254
Methyl N-(2, 6-dibenzyloxybenzenesulfonyO-N-acetylglycinate 25. A solution of 22a (0.93 g, 2.1 mmol) in Ac20 (40 ml) and fused sodium acetate (0.8 g) was refluxed for 3 h, then diluted with water and washed with EtOAc. The combined organic phases were washed with 1 M aq. KOH and water, dried and evaporated. Flash chromatography [EtOAc-hexanes (2:3] gave 25 as white crystals (0.93 g, 82%), mp 109-110 °C (EtOAc- hexanes): IR (Nujol) 1750, 1690, 1370, 1095 cm~; ~H NMR (90 MHz) 87.24-7.56 (m, 11H), 6.68 (d, d8, 2H), 5.16 (s, 4H), 4.17 (s, 2H), 3.63 (s, 3H), 2.29 (s, 3H). Calcd for C25H25NOTS: C, 62.10; H, 5.21; N, 2.90. Found: C, 62.10; H, 5.17; N, 2.87.
Methyl N-(2,6-dihydroxybenzenesulfonyl)-N-acetylglycinate 26. A solution of 25 (0.82 g, 1.7 mmol) in EtOH (50 ml) was stirred with 10% Pd-C (0.35 g) under hydrogen as described for compound 17a. Flash chromatography [EtOAc-hexanes (3:2)] gave 26 as a white solid (0.39 g, 76%): ~H NMR (90 MHz, CDCI 3- DMSO-d6) 5 7.28 (t, J 8, 1H), 6.48 (d, d 8, 2H), 4.60 (s, 2H), 3.76 (s, 3H), 2.34 (s, 3H). Attempted recrystallisation (EtOAc-hexanes) resulted in equilibration with the 2-O-acetyl isomer (see Discussion).
Methyl N-[2,6-bis(methoxycarbonylmethoxy)benzenesulfonyl]glycinate 28. A solution of 24e (2.36 g, 4.5 mmol) in MeCN (90 ml) was treated at 0 °C with a solution of ceric ammonium nitrate (7.40 g, 13.5 mmol) in water (60 ml) and the mixture was stirred at 0 °C for 3 h. The solution was diluted with EtOAc and washed with water. The organic phase was washed successively with saturated aq. NaHCO3, saturated aq. Na2SO 3 and brine, dried and evaporated. Flash chromatography [EtOAc-hexanes (3:2)] gave 28 as white crystals (1.63 g, 89%), mp 101-102 °C (EtOAc-hexanes): UV (EtOH) 2m,x/nm 287 (dMlcm t 4400); UV [EtOH-25 mM ammonium phosphate, pH 7 (5:95)] 2mJnm 289 (dM~cm ~ 4600); IR (Nujol) 3220, 1755, 1740, 1335, 1115 cm~; IH NMR (90 MHz) ~7.16-7.36 (m, 2H), 6.65 (d, d 8, 2H), 4.76 (s, 4H), 3.96 (d, d6, 2H), 3.81 (s, 6H), 3.57 (s, 3H). Calcd for C~sH~gNOt0S: C, 44.44; H, 4.72; N, 3.45. Found: C, 44.24; H, 4.72; N, 3.38.
N-[2,6-Bis(carboxymethoxy)benzenesulfonyl]glycine 13. A mixture of 28 (811 mg, 2 mmol) in MeOH (36 ml) and 5 M aq. NaOH (4 ml) was refluxed for 2 h. The solution was cooled to rt and the residue was diluted with water, acidified with conc. HC1, saturated with NaCI and extracted with EtOAc. The combined organic layers were dried and evaporated to give a white solid. Recrystallisation gave 13 as white crystals (508 mg, 70%), mp 204-205 °C (acetone-hexanes): UV (25 mM ammonium phosphate, pH 7.0) ~ J n m 291.5 (dMJcm t 5100); IR (Nujol) 3285, 3250, 1760, 1740, 1720, 1315, 1120 cm~;~H NMR (400 MHz, DMSO-d~) 7.55 (t, d 5.7, 1H), 7.41 (t, J 8.2, 1H), 6.67 (d, .l 8.2, 2H), 6.52 (br s, 3H), 4.73 (s, 4H), 3.75 (d, d 5.7, 2H). Calcd for C12HI3NOIoS: C, 39.67; H, 3.61; N, 3.85. Found: C, 39.84; H, 3.62; N, 3.67.
Photolysis conditions. Solutions of compounds for photolysis (i.e. 2-4, 12, 13 and Notosylglycine) were prepared at 0.5 mM concentration ± naphthalene bisphosphate 11 (0.5 mM) in 25 mM ammonium phosphate, pH 7.0. Aliquots (0.2 ml) were irradiated in a 1 mm path length cell, using light from a 100 W xenon arc lamp which passed through a Hoya U340 filter betbre illuminating the cell. The extent of conversion of starting compounds was determined by HPLC analysis (Table 3). Quantification was based on peak heights compared to those of unphotolysed controls. Yields of free amino acids were determined on an automated amino acid analyser.
G. Papageorgiou, J. E. T. Corrie /Tetrahedron 55 (1999) 237-254 253
T a b l e 3. Conditions for HPLC analysis Compound Column Detection
wavelength (nm) 2 RP8 230 3 RP8 230 4 RP8 230
N-Tosylglycine RP8 230
10 RP8 313
11 RP8 313
12 SAX 284 13 RP8 284
19 SAX 284
Mobile Phase tR (min) tR of 11 (min)
500 mM NH4 phosphate, pH 5.8 4.6 .a 100 mM NH4 phosphate, pH 5.8 6.6 _a
25 mM NH4 phosphate, pH 5.8 + 5.8 44 5% MeCN 25 mM Na phosphate, pH 4.0 + 7.2 3.6 20% MeCN 25 mM Na phosphate, pH 5.5 + 3.2 b 10% MeCN 25 mM NH4 phosphate, pH 5.8 + 10.2 10% MeCN 125 mM NH 4 phosphate, pH 4.0 5.7 15.2 100 mM NH 4 phosphate, pH 4.0 5.8 -" + 10% MeOH 125 mM NH 4 phosphate, pH 4.0 1.6 b
a Compound 11 retained >50 min on column. b Compound 11 not co-injected.
ACKNOWLEDGEMENTS
We are grateful to the MRC Biomedical NMR Centre for access to facilities and to Dr. V.R.N. Munasinghe for recording NMR spectra. We thank Dr. K.J. Welham (School of Pharmacy, University of London) and Dr. S.A. Howell (NIMR) for mass spectral data and Mr. P. Sharratt (Biochemistry Department, University of Cambridge) for assistance with amino acid analysis. This work was supported by the Medical Research Council under the Neurosciences Approach to Human Health Initiative.
R E F E R E N C E S
1. Corrie, J.E.T.; Trentham, D.R. In Biological Applications of Photochemical Switches; Motrison, H., Ed.; Wiley: New York, 1993; pp 243-305.
2. Kaplan, J.H.; Forbush, B.; Hoffman, J.F. Biochemistry, 1978, 17, 1929-1935. 3. (a) Ramesh, D.; Wieboldt, R.; Niu, L.; Carpenter, B.K.; Hess, G.P. Proc. Natl. Acad. Sci. USA 1993, 90,
11074-11078; (b) Gee, K.R.; Wieboldt, R.; Hess, G.P.J. Am. Chem. Soc. 1994, 116, 8366-8367; (c) Wieboldt, R.; Ramesh, D.; Carpenter, B.K.; Hess, G.P. Biochemistry, 1994, 33, 1526-1533; (d) Wieboldt, R.; Gee, K.R.; Niu, L.; Ramesh, D.; Carpenter, B.K.; Hess, G.P. Proc. Natl. Acad. Sci. USA 1994, 91, 8752-8756; (e) Gee, K.R.; Niu, L.; Schaper, K.; Hess, G.P.J. Org. Chem. 1995, 60, 4260-4263.
4. Givens, R.S.; Jung, A.; Park, C.H.; Weber, J.; Bartlett, W. J. Am. Chem. Soc. 1997, 119, 8369-8370. 5. Rossi, F.M.; Margulis, M.; Tang, C.M.; Kao, J.P.Y.J. Biol. Chem. 1997, 272, 32933-32939. 6. (a) Corrie, J.E.T.; DeSantis, A.; Katayama, Y.; Khodakhah, K.; Messenger, J.B.; Ogden, D.C.; Trentham,
D.R.J. Physiol. 1993, 465, 1-8; (b) Papageorgiou, G.; Corrie, J.E.T. Tetrahedron 1997, 53, 3917-3932. 7. Corrie, J.E.T.; Papageorgiou, G. J. Chem. Soc., Perkin Trans. 1 1996, 1583-1592. 8. (a) Hamada, T.; Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc. 1986, 108, 140-145; (b) Hamada, T.;
Nishida, A.; Yonemitsu, O. Tetrahedron Lett. 1989, 30, 4241-4244. 9. Davidson, R.S.; Steiner, P.S.J. Chem. Soc. (C) 1971, 1682-1689. 10. Snieckus, V. Chem. Rev. 1990, 90, 879-933.
254 G. Papageorgiou. J. E. T. Corrie / Tetrahedron 55 (1999) 237-254
11. (a) Birch, A.J.; Corrie, J.E.T.; MacDonald, P.L.; Subba Rao, G. J. Chem. Soc., Perkin Trans. 1 1972, 1186-1193; (b) Kalivretenos, A.; Stille, J.K.; Hegedus, L.S.J. Org. Chem. 1991, 56, 2883-2894.
12. Backes, B.J.; Virgilio, A.A.; Ellman, J.A.J. Am. Chem. Soc. 1996, 118, 3055-3066. 13. Yoshimura, J.; Yamaura, M.; Suzuki, T.; Hashimoto, H. Chem. Lett. 1983, 1001-1002. 14. Lebouc, A.; Martigny, P.; Carlier, R.; Simonet, J. Tetrahedron 1985, 41, 1251-1258. 15. Kossai, R.; Emir, B.; Simonet, J.; Mousset, G. J. Electroanal. Chem. 1989, 270, 253-260. 16. (a) Hiller, K.O.; Masloch, B.; G6bl, M.; Asmus, K.D. J Am. Chem. Soc. 1981, 103, 2734-2743; (b)
MOnig, J.; Chapman, R.; Asmus, K.D.J. Phys. Chem. 1985, 89, 3139-3144. 17. (a) Pincock, J.A.; Jurgens, A. Tetrahedron Lett. 1979, 1029-1030; (b) Badr, M.Z.A.; Aly, M.M.; Fahrny,
A.M.J.. Org. Chem. 1981, 46, 4784-4787. 18. Givens, R.S.; Levi, N. In The Chemistry of Functional Groups, Suppl. B. The Chemistry of Acid
Derivatives; Patai, S., Ed.; Wiley: Chichester, 1979; pp 641-753. 19. (a) Bruncko, M.; Crich, D. J. Org. Chem., 1994, 59, 4239-4249; (b) McDonald, F.E.; Danishefsky, S.J. J
Org. Chem., 1992, 57, 7001-7002; (c) Garigipati, R.S.; Adams, J.L. PCT lnt. Patent Appl. WO 9630337 (Chem. Abstr. 1996, 125, 32828).
20. Pettit, G.R.; Kadunce, R.E.J. Org. Chem. 1962, 27, 4566-4570; Abe, K.; Tsukamoto, Y.; Ishimura, A. J. Pharm. Soc. Jpn. 1953, 73, 1319-1322 (Chem. Abstr. 1955, 49, 177).
21. Adger, B.M.; Young, R.G. Tetrahedron Lett. 1984, 25, 5219-5222; Rousseau, V.; Lindwall, H.G.J. Am. Chem. Soc. 1950, 72, 3047-3051; Sianesi, E.; Redaelli, R.; Bertani, M.; Da Re, P. Chem. Ber. 1970, 103, 1992-2002; Sienesi, E.; Setnikar, I.; Massarani, E.; Da Re, P. Get. Patent 2,022,694 (Chem. Abstr. 1971, 74, 141829).
22. Lafon, L. Ger. Patent 2,038,836 (Chem. Abstr. 1971, 75, 35528); Whittaker, K. Br. Patent 926,999 (Chem. A bstr. 1963, 59, 11716).
23. Todd, D.; Teich, S. d. Am. Chem. Soc. 1953, 75, 1895-1900. 24. Blanco, M.; Perillo, I.A.; Schapira, C.B.J. Heterocycl. Chem. 1995, 32, 145-154. 25. Kametani, T.; Fukumoto, K. J. Chem. Soc. 1964, 6141-6146. 26. Takahashi, I.; Nomura, A.; Kitajima, H. Synth. Commun. 1990, 20, 1569-1575. 27. Uhlmann, E.; Engels, J. Tetrahedron Lett. 1986, 27, 1023-1026; Bannwarth, W.; Trzeciak, A. Helv. Chim.
Acta 1987, 70, 175-186. 28. Cleaver, L.; Nimgirawath, S.; Ritchie, E.; Taylor, W.C. Aust. J. Chem. 1976, 29, 2003-2021. 29. Rowe, E.J.; Kaufman, K.L.; Piantadosi, C. J. Org. Chem. 1958, 23, 1622-1624. 30. Testa_fed, L.; Tiecco, M.; Tingoli, M.; Montanucci, D. Tetrahedron 1982, 24, 3687-3692.